The aim of this proposal is to examine the role of peptidergic neurons of the myenteric plexus in the regulation of small intestinal and colonic peristalsis in the guinea pig and rabbit. The activity of neurons containing vasoactive intestinal peptide (VIP), enkephalin, dynorphin and somatostatin, and their interaction with each other and with regulatory cholinergic interneurons will be examined using vascularly perfused ileal and colonic segments that permit vascular sampling orad and caudad to central distension stimulus. Peptide release will also be examined in muscle strips containing intact myenteric plexus or severed axonal projections. JA model of peristalsis based on the topography of peptidergic neurons in the myenteric plexus and circular muscle is proposed to serve as a basis for experimental analysis. The main components of the model as they relate to peptidergic neurons are as follows: 1. VIP neurons projecting caudad into myenteric plexus and circular muscle are the mediators of aboral relaxation during peristalsis; 2. Enkephalin/dynorphin neurons projecting orad into myenteric plexus and caudad into circular muscle regulate the activity of VIP neurons, acting chiefly to inactivate these inhibitory neurons; 3. Somatostatin neurons projecting caudad within the myenteric plexus but not into circular muscle act as facilitatory interneurons that intensify the activity of VIP neurons; and 4. These peptidergic neurons receive input from a network of cholinergic interneurons via nicotinic and possibly muscarinic M1 ganglionic receptors. The participation of these peptidergic neurons will be identified by : 1. measurement of peptide release during peristalsis from whole segments as well as from segments orad and caudad to a central distension stimulus; 2. measurement of peristaltic activity in the presence of specific antagonists and antisera (naloxone and Mr2266 for enkephalin and dynorphin neurons, VIP and somatostatin antisera, and the selective M1 and M2 muscarinic antagonists, pirenzepine and 4-DAMP); and 3. Measurement of peptide release from isolated muscle strips with intact myenteric plexus or severed axonal projections. The approach described in the present proposal is an attempt to study the role of peptidergic neurons in the regulation of an important motor function of the gut.